Deciphering g-protein-coupled receptor 119 agonists as promising strategy against type 2 diabetes using systems biology approach

Official URL: https://dx.doi.org/10.1021/acsomega.8b01941

Type 2 diabetes (T2D) has been established as a serious and chronic medical condition with clinical feature of insulin deficiency and the resultant pathologically high glucose level in blood. Among various approaches purposed for T2D treatment, small molecule like agonist for G-protein-coupled receptor 119 (GPR119) was suggested to regulate blood glucose level by stimulating pancreatic β-cells function. This study employed homology and threading modeling approach to predict the GPR119 structure and conducted the structure-based virtual screening (SBVS) to discover novel agonist for GPR119 signal activation. Although the SBVS approach concluded a total of 419 compounds, we selected only 10 compounds for validation based on their docking scores (threshold values were fixed between -16.23 and -10.00) with GPR119 active site. Further, biochemical pathway simulation was also conducted for T2D involving GPR119 and 10 screened compounds using system biology approach. However, we observed that only compound 1 (C23H29F3O6), with characteristics such as docking score of -16.227, MMGBSA value of -66.23, exhibiting attraction for GLN65, ARG71, and THR86 residues, and optimum concentration of 0.50 μM, has the potential to activate GPR119 signaling and subsequently regulated the glucose-dependent insulin secretion in blood. Hence, this novel compound 1 has vindicated its capacity for further development as a potential therapeutic agent in the treatment of T2D.